The identification and design of highly selective agonists and antagonists for CNS-related G coupled protein receptors (GPCRs) is of paramount importance for the development of new drugs to well-known GPCR targets and for the clinical validation of new targets for a wide range of mental disorders. The long term goal of our project is to capitalize on the recent breakthroughs in GPCR crystal structure determination and to use advanced molecular modeling to create and validate an efficient in silico GPCR ligand affinity/selectivity profiling panel (GLASP panel) for applications to the computer assisted rational design of subtype selective drug candidates. In year one of Phase I, we plan to develop and validate the GLASP panel for amine binding families of CNS-related GPCR targets with the closest structural and functional homology to the recently solved b2-adrenergic (b2AR) high resolution 3D template. We will build detailed all-atom models of all GPCR subtypes in adrenergic, serotonin and dopamine families, taking into account conformational flexibility and ligand-induced plasticity of receptors. The individual models and the whole affinity/selectivity panel will be optimized and verified with a comprehensive set of publicly available ligand affinity data. In addition, we plan to strictly validate the GLASP panel though blind prediction of affinity for a selected set of ligands, followed by biochemical testing and assessment of the panel accuracy by a third party. In year two, we plan to employ the validated in silico profiling panel in several rational drug design applications. Thus, we will use these tools to perform computer assisted lead optimization for targets selected by our partners in pharmaceutical industry. In addition, simplified versions of the all-atom models will be prepared and validated for fast virtual ligand screening (VLS) applications. The VLS models will be used to search large libraries of available and virtual compounds, and a selected focused library will be screened in biochemical assays to identify new lead candidates. The validated GLASP panel and fast VLS models will provide powerful tools for the cost-efficient rational design of novel high-affinity scaffolds and subtype selective agonists and antagonists for clinically important GPCR targets. Upon success of the Phase I project, we envision further extension of this approach to other CNS-related Class A GPCRs, and application to a number of collaborative programs in pharmaceutical industry and academia. PUBLIC HEALTH RELEVANCE: About half of the medications for mental disorders and neurodegenerative diseases target G-coupled Protein Receptors (GPCRs), but many of these drugs have serious side effects through "off target" activity with other GPCRs in the central nervous system (CNS) or the cardiovascular system. Improvement of existing treatments and development of new treatments for CNS targets depend on the design of highly selective molecules acting on one specific GPCR subtype. Recent breakthrough developments in GPCR atomic structure determination and improved molecular modeling tools make it possible to create and validate efficient applications for computer assisted rational design of new candidate drugs, which is the prime goal of our project.